Spirocyclic hydrazine imides



United States Patent 3,200,118 SFIROfiYCLlC HYDRAZINE IMIDES Charles H. Grog-an, Falls Church, Va, and Leonard M. Rice, Baltimore, Md, assignors to The Geschiclrter Fund for Medical Research, Washington, D.C., a corporation of New York No Drawing. Filed Oct. 31, 1961, Ser. No. 143,862 6 Claims. (Cl. 260-2472) This invention relates to novel synthetic organic compounds having significant pharmacological activlty, particularly pharmacological activity producing ellects on the nervous and cardiovascular systems. More specifically, this invention relates to derivatives of hydrazine in which a portion of the hydrazine molecule, namely one nitrogen atom, is combined into a cyclic ring structure, said cyclic ring structure being further characterized in that it is an azaspirane structure.

A primary object of this invention is to provide novel synthetic organic compounds having significant pharmacological activity producing effects on the nervous and cardiovascular systems.

7 Another object of this invention is to provide N-amino azaspirane diones, N-aminoazaspiranes and methods for synthesizing these novel types of compounds.

Another and equally important object is to provide novel N-amino azaspirane diones and N-aminoazaspiranes having pharmacological properties which render them valuable as medicinal products.

These and other objects and advantages of the present invention will become more apparent upon reference to the ensuing description and appended claims.

Formula 1 depicts the general structural formula of one class of the novel compounds of the present invention, the N-aminoazaspirane diones:

on ring B.

Ring A comprises a mono or polycyclic ring system oi at least 5 atoms. While there is no particular limit' on the number of atoms in ring A, a ring of from 5-15 atoms is preferred. Ring B comprises a heterocyclic ring of 5 or 6 atoms, one of which is nitrogen, the two carbonyl carbons being adjacent to the nitrogen atom. The other atoms of ring B are preferably carbon atoms. Element (c) is a spiro carbon atom connecting ring structures A and B. Element ((1), namely the substituent X on ring A, represents one or more atoms and/ or radicals of the group consisting of hydrogen, alkyl, alkenyl, alkoxy, aryl and cycloalkyl. While the invention is not so restricted, the alkyl, alkenyl and alkoxy radicals preferably contain no more than 6 atoms in their chain. Constituent Y in ring A is an atom selected from the group consisting of carbon, oxygen and sulfur. In element (f), R and R are substituents on the exocyclic nitrogen atom selected from the group consisting of allzyl, alkenyl, cycloalkyl and aryl containing up to 10 carbon atoms. R and R may be the same group or any combination of the groups listed above.

For example, R and R may be selected so that the following combinations of groups are on the exocyclic nitroen portion of the hydrazine molecule: dimethyl, dihexyl,

5 mcthyl-allyl, diallyl, methyl-phenyl, diphenyl, ethyl-cyclohexyl, dicyclohexyl, methyl-p-chlorophenyl, di-p-chlorophenyl, etc. In addition to the above, the grouping substituent is such as to permit that reactant to react under the prevailing reaction conditions to form the desired dione structures.

The N-substituted-N-aminoazaspirane diones may be reduced by suitable means to yield the corresponding N- aminoazaspirane bases shown by Formula 2:

r A c a n-nf In this formula, the same significance is attached to all of the symbols'used to define the structure of the diones shown by Formulal. The only difierence between Formula 1 and Formula 2 is that the latter has had the oxygen atoms removed from the carbonyl groups by reduction.

Generally speaking, the novel compounds of the present invention are obtained by reacting the appropriate N,N-disubstituted hydrazine or N-amino heterocycle withan anhydride selected from the group consisting of mono or polycyclic gem-carboxy acetic and gem-diacetic anhydrides and cyclizing the initially formed arnic acid to the desired dione. The process is illustrated by the following equation: 7 1

Y c o le um" If, Z1! 2 R1 ZOH From this equation it will be seen that the anhydride, in which one or both of Z and Z may be acetyl, depending on whether or not one is using a carboxy-acetic or diacetic anhydride, is reacted with the hydrazine. The reaction is exothermic and the anhydride ring is ruptured to form the amic. acid which, on heating to an appropriate temperature, loses Water and undergoes ring closure to form the desired azaspirane dione. The temperature generally required to effect such ring closure is in the range of 140-220" C., a range of 180-220" C. being preferred.

The following hydrazines may be cited by way of illustrating some of these that may be employed as one of the reactants in the general synthesizing procedure: N,N- dimethyl; N,N-diethyl; N,N-dihexyl; N,N-dibutyl; N- methyl-N-hexyl; N,N--diphenyl; N-cyclohexyLN-methyl; N,N-dicyclohexyl; N-amino-4-methyl piperazine; N- aminomorpholine; N-aminopyrrolidine; N-aminopiperidine; N-amino-2-methylpiperidine; N-amin-3,5 dimethylmorpholine; N-amino 2,6 dimethylmorpholine; etc. Likewise a wide variety of cyclic gem-carboxy-acetic and gem-diacetic anhydrides may be employed as a reactant. Illustrative of some of these are the following: cyclo hexane-l-carboxy-l-acetic; cyclohexane-l,l-diacetic; 3- methylcyclohexane-l-carboxy-l-acetic; 3 methylcyclohexane 1,1 diacetic; 3-allyl-cyclohexane-l-carboxy-1- carboxy-l-acetic; 4-methylcyclohexane-l-carboxy-l-acetic; 4-methylcyclohexane-1,1-diacetic; 4-methoxycyclohexanel-carboxy-l-acetic; 4-methoxycyclohexane-1,l-diacetic 4- t-butylcyclohexane-l-carboxy-l-acetic; 4 t butylcyclohexane-1,1-diacetic; 4-cyclohexylcyclohexane-l-carboxyl-acetic; 4-cyclohexylcyclohexane-1,1-diacetic; cyclopentane-l-carboxy l acetic; cyclopentane l,1,- diacetic; 3- methylcyclopentane 1 carboxy 1 acetic; 3- methylcyclopentane 1,1 diacetic; cyclopheptane 1 carboxyl-acetic; cycloheptane-l,l-diacetic; cyclooctane-l-carboxy- 1 acetic; cyclopentadecane 1 carboxy-l-acetic; transhexahydrohydn'ndene-2-carboxy-2-acetic; trans hexahydrohydrindene-2,2-diacetic; ,4 phenylcyclohexane-l-carboxy 1 acetic; 3 triacyclopentane 1 carboxy- 1 acetic; 3 thiacyclopentane 1,1 diacetic; 4-triacyclohexane-l-carboxy l-acetic; 4-thiacyclohexane-1,1-diacetic; 4-oxacyclohexane-l-carboxy-l-acetic; 4-oxacyclohexane- 1,1-diacetic; 3,5 dimethyl-4 oxycyclohexane-1-carboxy-l acetic; 3-methyl-S-phenyl-4-oxacyclohexane-l-carboxy-1- acetic; 3,5-dimethy1-4-oxacyclohexane-1,1-diacetic anhydrides. The foregoing substances, listed by way of illustration of the substances that may be used as reactants in the foregoing equation, are intended to be illustrative of the wide scope of the reactants employable and products obtained therefrom, but are in no way intended to be restrictive.

In addition to the azaspiranes and azaspirane diones set forth above in Formulae ,1 and 2, the instant invention additionally contemplates the treatment of the basic azaspiranes to form simple acid addition and quaternary salts. Formulae 3 and 4 illustrate the type and site of salt formation resulting from the appropriate treatment of.

the azaspirane bases of the present invention:

f R 1 (A? Y A. B it I Formula 4 illustrates the simple salt formation resultt ng from the salting of the basic azaspiranes with nonl toxic acid anions, such as chloride, iodide, bromide, sulfate, acetate, succinate, maleate, phosphate',-benzoate, lactate, thiodisalicylate, mucate,.citrate, tartrate and the like. In general, those non-toxic salts of the basic azaspiranes which are soluble in Water or otther well-tolerated solvents are particularly useful for therapeutic purposes due to the ease of administration of the salts in their dissolved form. In addition, other non-toxic salts may also be used.

Formula 3 illustrates quaternary salt formation resulting from quaternizing the basic azaspiranes with alkyl esters. As shown, R represents an alkyl, alkoxyalkyl or alkenyl radical of 1 to 22 chain atoms. The anion, A,

may be any of the non-toxic anions useful informing the simple acid addition salts :as discussed above in connection with Formula 4.

The compounds illustrated by Formulae 1-4 have been shown to possess pharmacological activity affecting the nervous and cardiovascular systems- Specifically, the

- ic solvents, the smaller molcules are soluble in petroleum ether to a moderate extent and are considerably soluble in Warm (Ml-"60 C.) petroleum ether. At the same time, they are moderately soluble in'cold water and very soluble in warm water. This combination of solubility in hydrophobic as well as hydrophilic media permits these compounds to be distributed widely in both types of media in physiological systems.

By Way of illustration, the compound Z-dimethylamino- 2-azaspiro[4.4]nonane-1,3-dione (Example I) may be dissolved in sterile water or isotonic saline and administered in aqueous medium as a topical or local anesthetic by injection of the 1 or 2% solution. The pH of these aqueous solutions is nearly neutral. Alternatively, the compound maybe dissolved in oily vehicles for depot activity or may be administered while dissolved in propylene glycol, ethanolamine-water, N-ethylethanolamine water, or other media suitable for intravenous, intramuscular or subcutaneous administration.

The compound of Example II, when administered intravenously or intramuscularly, produces a gradual and prolonged depression of the blood pressure without noticeable ganglioplegic effects. The compoundalso produces prolonged depression of the blood pressure without ganglioplegic effects when administered orally.

The free bases and their acid addition and'quaternary salts possess in varying degree anti-inflammatory and antihistaminic properties. They may be administered in doses at -100 mg. orally orintramuscularly one-to two times at y. a

The following examples illustrate the method of prepa ration of the compounds of the present invention:

EXAMPLE I A. Z-dimethylamino-Z-azaspiro[4.4] n0nane-],3-dione melted at 5455 C. Recrystallization from ligroin gave long needles with M.P. 55-5 6 -C.

B. The hydrochloride The above imide, when dissolved in ether and treated with gaseous hydrogen chloride, gave an immediate precipitate. This was filtered and dried with suction. As initially precipitated it melted at 8487 C. The hydrochloride is unstable and gradually loses hydrogen chloride and reverts to the original imide. On drying in vacuo or in an oven, the process of decomposition is accelerated. On vacuum drying, all that is recovered is the original imide Which sublimes during drying and is completely devoid of the hydrochloride salt in a few hours.

EXAMPLE II 3 -dimethylami.'z0-3 -azaspir'0 [5 .5 undecane-ZA-dione Reaction of 18.2 gm. (0.1 mole) of cyclohexane-1,1- diacetic acid anhydride With excess dimethyl hydrazine as described in Example I yielded the title compound in 98% yield with a melting point of 118120 C. Recrystallization from water gave a product with a M.P. of 118.5- 1 19.5 C.

EXAMPLE III A. 3-az'methylamino-3-azaspir0 [5 .5 undecane Reduction of 20 gm. of the imide from Example II with lithium aluminum hydride in anhydrous ether. yielded the title base in 85% yield with a boiling point of 73-75" C./ 0.1 mm.

B. The hydrochloride EXAMPLE V 2-di methy lami 110-2 -azaspi r0 7.4 dodecane-Z ,3-dione Reaction of 12 gm. (0.06 mole) of the anhydride of cyclooctane-l-carboxy-l-acetic acid with unsym. dimethylhydrazine as described in Example I gave the title imide in 98% yield (B.P. 108-112" C./0.15 mm.).

EXAMPLE VI 3 -dimetlzylamin0-3 -azaspiro [4 .5 decane-2,4-dione Reaction of gm. (0.06 mole) of the anhydride of cyclopentane-l,l-diacetic acid with excess unsym. dimethylhydrazine as described in Example I yielded the title imide quantitatively with a M.P. of 5254 C. Recrystallization from petroleum ether gave a product with a M.P. of 6l62.5 C.

EXAMPLE VII Z-dimethylamino-Z-azaspiro [5.4] decane1,3-di0ne Reaction of the anhydride of cyclohexane-l-carboxyl-acetic acid with unsym. dimethylhydrazine as described in Example I yielded the title imide quantitatively with a M.P. of 94102 C. Recrystallization from petroleum ether gave a product with a M.P. of 103-104 C.

EXAMPLE VIII 2-dimezhylamino-7-thia-2-azaspir0-[4.4] n0nane-1,3-di0-ne Reaction of 10 gm. (0.058 mole) of S-thiacyclopentanel-carboxy-l-acetic acid anhydride and an excess of unsym. dimethyl hydrazine as described in Example I gave a quantitative yield of the title compound (M.P. 8692 C.). Two recrystallizations from acetone-petroleum ether gave a product with a M.P. of 9494.5 C.

6 EXAMPLE IX 3 -dimethylamino-9-t-butyl-3-azaspir0 [5 .5 undecane- 2,4-di0ne This compound was prepared in quantitative yield as described in Example I from the anhydride of 4-t-butylcyclohexane-1,1-diacetic acid and excess unsym. dimethyl hydrazine and melted at 118-119 C.

EXAMPLE X Z-dimethylamino-Z-azasp=ir0 [6.4] undecane-l ,3-di0ne The title compound was obtained in quantitative yield as described in Example I from the anhydride of cycloheptane-l-carboxy-l-acetic acid and excess unsym. dimethyl hydrazine and melted at 8990 C.

EXAMPLE XI Spiro-trans-decalirt-Z,4'-piperidine-l '-dimethyl amin0-2',6'-dione This compound was obtained in quantitative yield from the anhydride of trans-decalin-2,2-diacetic acid and unsym. dimethyl hydrazine as described in Example I and melted at 102103 C.

EXAMPLE XII 2-dimethylamino-7-methyl-2-azaspir0[4.4] nonane-I ,3-dione This compound was obtained in yield from the reaction of the anhydride of 3-methyl cyclopentane-lcarboxy-l-acetic acid and excess unsym. dimethyl hydrazine, It boiled at 88-90 C./0.15 mm. and melted at 45-46 C.

EXAMPLE XIII 2-m0rph0lino-2-azaspir0 [4.4] nonane-1,3-di0ne This compound was obtained by the reaction of N-aminomorpholine and the anhydride of cyclopentane-lcarboxy-l-acetic acid in quantitative yield and melted at 151-152 C.

EXAMPLE XIV 2-m0rpholino-2-azaspiro [4.4] nonane-1,3-dione This compound was obtained in quantitative yield as in Example XIII, using N-aminopiperidine in lieu of N- aminomorpholine, and melted at 79-80 C.

EXAMPLE XV 3-piperidin0-3-azaspiro[5 .5 undecan-e-2,4-di0ne This compound was obtained in quantitative yield as in Example XIV from N-aminopiperidine and the anhydride of cyclohexane-l,1-diacetic acid (M.P. l2l C.).

EXAMPLE XVI Z-piperidino-Z-azaspiro[6.4] undecane-.1,3-di0ne This compound was obtained in quantitative yield from N-aminopiperidine and the anhydride of cycloheptanel-carboxy-l-acetic acid as described in Example I and melted at 118-1l9 C.

EXAMPLE XVII 2-(2,6-dimethylmorpholino)-7-methyl-2-azaspiro [4.4]n0nane-l,3-di0ne This compound was obtained in quantitative yield from the reaction of the anhydride of 3-methylcyclopentanel-carboxy-l-acetic acid and N-amino-2,6-dimethyl morpholine and melted at 7475 C.

EXAMPLE XVIII 2- (2,6-dimethylmorpholino)-2-azaspir0 [6.4] undecane-1,3-di0ne This compound was obtained as in Example XVII from the anhydride of cycloheptane-l-carboxy-l-acetic acid in quantitative yield and melted at 109-110 C.

7 EXAMPLE XIX Z-dibutylamina-Z-azaspz'ro[4.4]n0nane-1,3-di0ne This compound was obtained in 86% yield from reaction of unsym. di-n-butyl hydrazine and the anhydride of cyclopentane-l-carboxy-l-acetic acid and boiled at EXAMPLE XX Z-pyrrolidino-Z-azaspiro [4.4] nonane-L3-di0ne This compound was obtained in quantitative yield as in Example I using the anhydride of cyclopentane-l-carboxy-l-acetic acid and N-amino pyrrolidine and melted The invention may be embodied in other specific forms without departing from the spirit or essential characwherein A is selected from the group consisting of mono and polycyclic rings of at least five ring atoms, said ring atoms other than Y being carbon; Y is selected from the group consisting of C, O and S; X is. at least one of the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkoxy, cycloalkyl of up to 6 'ring atoms and monocarbocyclic aryl; B is a saturated ring of 5-6 atoms whose ring atoms other than the nitrogen atom are carbon atoms; and R and R are selected from the group consisting of lower alkyl, lower alkenyl, cycloalkyl of up to 6 ring atoms and monocarbocyclic aryl of up to 10 carbon atoms, and, together with the nitrogen atom to which they are attached, form a member selected from the group consisting of morpholino, pyrrolidino, piperidino and piperazino. 2. 2-dimethylamino-Z-azaspiro(4.4)nonane-1,3-dione.

3. 3-dirnethylamino-3-azaspiro( 5 .5 undecane-ZA-dione. 4. Z-dimethylamino-2-azaspiro(7.4)dodecane-l,3-dione. 5. 2-morpholino-2-azaspiro (4.4) nonane-l ,3-dione. 6. 2-piperidino-2-azaspiro (4.4) nonane-1,3-dione.

References Cited by the Examiner UNITED STATES I ATENTS 2,953,562 9/60 Schiller et a1. 260247.2 2,980,674 4/61 Alberti et a1. 260247.2 3,000,895 9/61 Frankel 260293 3,010,965 11/61 Elpern 260-293 NICHOLAS S. 11122;), Fri/nary Examiner.

IRVING MARCUS, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,200,118 August 10, 1965 Charles H. Grogan et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, lines 24 and 25, strike out "l-carboxy"; line 38, for "triacyclopentane" read thiacyclopentane line 39, for "4-triacyclo-" read 4-thiacyclocolumn 4, line 5, for "otther" read other line 29, for "molcules" read molecules same column 4, line 69, for "SQ-97 C." read 89-9l C. column 6, line 42, for "2-morpholino", in italics, read 2-piperidino in italics.

Signed and sealed this 1st day of February 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA 